Exploring neurodegenerative disease-associated gene function in iPS-microglia

University of Oxford Sir William Dunn School of Pathology

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Prof W S James, Dr S Cowley No more applications being accepted Competition Funded PhD Project (Students Worldwide)

Oxford United Kingdom Biochemistry Cell Biology Genetics Immunology Microbiology Molecular Biology Pathology Virology

About the Project

Microglia are brain parenchyma-resident macrophages, with important homeostatic functions, clearing away dead cells and debris, and remodelling defunct neuronal connections. They are strongly implicated in the progression of Alzheimer’s and other neurodegenerative diseases, with several key Alzheimer’s-associated genes expressed not in neurons but specifically in microglia. We have developed a genetically tractable system for differentiating authentic human macrophages and microglia from pluripotent stem cells, which is used widely to investigate disease pathogenesis and identify new therapeutic targets [1-4]. You will use human iPS microglia to investigate the role of one of these neurodegenerative disease-associated genes. Using the latest CRISPR/Cas9 technology to knockout and/or introduce precise mutations, you will be able to dissect the molecular interactions and regulatory pathways through which these genes mediate neuroinflammation and disease progression.

Funding Notes

4 Year DPhil Prize Studentships cover full University fees, a tax free enhanced stipend of ~£20,168 pa, and up to £5,300 pa for research costs and travel. The competition is open to applicants from all countries. See https://www.path.ox.ac.uk/content/prospective-graduate-students for full details and to apply.

References

1. Haenseler, W., et al., A Highly Efficient Human Pluripotent Stem Cell Microglia Model Displays a Neuronal-Co-culture-Specific Expression Profile and Inflammatory Response. Stem Cell Reports, 2017. 8(6): p. 1727-1742.
2. Hedegaard, A., et al., Honing the Double-Edged Sword: Improving Human iPSC-Microglia Models. Frontiers in Immunology, 2020. 11.
3. Washer, S.J., et al., Single-cell transcriptomics defines an improved, validated monoculture protocol for differentiation of human iPSCs to microglia. bioRxiv, 2022: p. 2022.08.02.502447.
4. Hall-Roberts, H., et al., TREM2 Alzheimer’s variant R47H causes similar transcriptional dysregulation to knockout, yet only subtle functional phenotypes in human iPSC-derived macrophages. Alzheimer's Research & Therapy, 2020. 12(1): p. 151.

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